Ultra-Hypofractionated vs. Moderately Hypofractionated Proton Therapy for Early Breast Cancer After Lumpectomy

A Prospective Phase II Randomized Controlled Trial Comparing Ultra-Hypofractionated and Moderately Hypofractionated Proton Radiotherapy Following Breast-Conserving Surgery in Early-Stage Breast Cancer（UPH-BC）

Breast-conserving surgery (BCS) followed by whole-breast irradiation (WBI) remains the standard therapeutic approach for early-stage breast cancer. Long-term follow-up data from the FAST trial (10-year analysis) demonstrated that the 28.5 Gy/5-fraction regimen exhibited comparable adverse effects to the conventional 50 Gy/25-fraction regimen, with no statistically significant differences in photographic cosmetic assessments at 2 and 5 years post-treatment. The FAST-Forward trial demonstrated comparable 5-year ipsilateral breast tumor recurrence rates (IBTR) and incidence of radiation-related toxicities between ultra-hypofractionated whole-breast irradiation (UH-WBI; 26 Gy in 5 fractions over 1 week) and moderately hypofractionated whole-breast irradiation (MH-WBI; 40 Gy in 15 fractions over 3 weeks). Additionally, no statistically significant difference in cosmetic outcomes was observed between the two regimens at the 2-year follow-up.

Proton radiotherapy enables precise dose delivery to tumor targets while minimizing radiation exposure to surrounding normal tissues, thereby reducing treatment-related toxicities. However, current clinical protocols predominantly employ conventional fractionation for proton therapy, with a paucity of robust evidence evaluating the efficacy and safety of ultra-hypofractionated proton radiotherapy in breast cancer patients. This prospective randomized controlled trial aims to establish high-level scientific evidence for the clinical application of ultra-hypofractionated proton radiotherapy following BCS, ensuring non-inferiority in oncologic control, toxicity profiles, and cosmetic preservation compared to standard regimens.

Inclusion Criteria:

1. Age ≥ 40 years
2. Pathologically (cytologically or histologically) confirmed unilateral primary invasive breast carcinoma
3. Breast conserving surgery + sentinel lymph node biopsy/axillary lymph node dissection, pathological stage pT1-2N0M0，negative margins (≥ 2 mm)
4. No distant metastasis confirmed by CT, MRI, bone scan, and PET/CT
5. No prior radiation therapy to the ipsilateral chest or breast
6. ECOG 0 ~ 2 or KPS ≥ 70

Exclusion Criteria:

1. Without pathology diagnosis
2. Positive margins or close margins (< 2mm)
3. Lymph nodes or distant metastasis
4. Bilateral breast cancer or patients with a history of contralateral breast cancer
5. Prior radiation therapy to the ipsilateral chest or breast
6. Pregnancy (confirmed by serum or urine β-HCG test) or lactation